Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10)

Am J Respir Crit Care Med. 2006 Jan 1;173(1):112-21. doi: 10.1164/rccm.200507-1058OC. Epub 2005 Sep 22.


Rationale: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents.

Objective: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs.

Methods: We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production.

Results: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype.

Conclusions: The results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / biosynthesis
  • Animals
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Bleomycin / pharmacology
  • Cell Culture Techniques
  • Cell Differentiation / physiology*
  • Fibroblasts / physiology*
  • Fibrosis / chemically induced
  • Fibrosis / genetics
  • Humans
  • Lung Diseases, Interstitial / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • PTEN Phosphohydrolase / biosynthesis
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / physiology*
  • Pulmonary Fibrosis / physiopathology*
  • Transforming Growth Factor beta / physiology


  • Actins
  • Antibiotics, Antineoplastic
  • Transforming Growth Factor beta
  • Bleomycin
  • PTEN Phosphohydrolase